Acetates of 3-piperidinol



2,995,560 ACETATES OF 3-PIPERIDINOL John H. Biel, Milwaukee, Wis.,assignor, by mesne assignments, to Lakeside Laboratories, Inc.,Milwaukee, Wis., a corporation of Delaware No Drawing. Filed Sept. 11,1959, Ser. No. 839,288 9 Claims. (Cl. 260-2943) This invention relatesto an ester of cyclic aminoalcohols and particularly to an acetic esterof N-ethyl-3- piperidinol and the salts thereof.

This application is a continuation-in-part of application Serial No.180,295, filed August 18, 1950, now abandoned, and Serial No. 217,413,filed March 24, 1951, now abandoned.

The reduction or smooth muscle spasm, whether of musculotropic orneurotropic, by atropine, and by various synthetic compounds related instructure to atropine or papaverine, is well known. While many of thesecompounds will eifectively abolish one or the other type of spasm, theyare not capable of relieving both types of muscle spasm. Furthermore,the action of the known compounds is usually accompanied by undesirableside eiieots such as dilatation of the pupil of the eye, dryness of themouth, large increase in rate of heart beat, hypotension, nausea, andvomiting.

Some esters of N-alkyl-4-piperidinol have been found to be activeanti-spasmodics or spasmolytics, but such esters have never been putinto use. It is well known that changes in the positions of certainsubstituents on the piperidine ring may produce profound differences inthe physiological activity and effects of such compounds, whichdifferences are not predictable. Thus, N-methyl-4-phenyl-4-propionoXy-piperidine is a potent analgesic, whereas, thecorresponding N-methyl-Z-phenyl-Z-propionoxy-pipen'dine has only slightanalgesic properties, and beta-4-methyl-piperidine-ethyl benzoate hasconsiderable anesthetic action while the 2- and 3-methyl derivativeshave no such action. Hence, it will be seen that shifting a group fromthe 4-position of the piperidine ring may cause complete loss ofactivity.

I have found that substituted acetic acid esters of N-ethyl-3-piperidinol are effective as an anti-spasmodic in bothmusculotropic and neurotropic spasms and have longer duration of actionwith fewer undesirable side eflects than various other anti-spasmodicsnow used.

It is, therefore, an object of the present invention to provide acompound for pharmaceutical purposes and having the effect of reducingeither involuntary muscle or nervous spasm.

Another object of the invention is to provide a compound having ananti-spasmodic effect in humans, which compound is long lasting inaction and which will have only a few undesirable side reactions ofminor importance.

A further object of the invention is to provide a series of substitutedacetic acid esters of N-ethyl-3-piperidinol having longer activity andside reactions both less in number and of lower intensity than othercompounds now in use for reducing spasm of human muscle or nerves.

Generally, the present invention includes the substituted acetic acidesters of N-alkyl-3-piperidinol and the salts thereof and thepreparation of such compounds by States atent O the use of simpleequipment and procedures. pounds conform to the type formula:

The como-o-cm S Ri where:

R is an alkyl radical R2 is H or OH where: R, and R are lower alkylradicals and X is an inorganic radical.

N-ethyl-B-piperidyl-diphenylacetate hydrochloride was formed by heatingequimolecular amounts of N-ethyl-3- piperidinol and diphenylacetylchloride in the presence of a solvent for the reactants. Thehydrochloride salt was precipitated and is readily purified byrecrystallization from a suitable solvent. The free baseN-ethyl-S-piperidyl diphenylacetate was obtained as an oily material, bytreating thesaid hydrochloride with sodium hydroxide. N-ethyl-3-piperidyl-diphenylacetate-methiodide was formed by treating freeN-cthyl-3-piperidyl-diphenylacetate in an ether solution with methyliodide.

N-methyl-3-piperidyl-diphenylacetate and its hydrochloride salt differfrom the preceding compositions by the substitution of a methyl group onthe N of the piperidine ring. The base was made by refluxing N-methyl-3-hydroxy-piperidine with diphenylacetyl chloride and pyridine.The refluxed material is neutralized and extracted with ether. Theextract was dried and the ether removed, and the base recovered byvacuum distillation. A solution of the base in ethereal hydrochloricacid precipitated the hydrochloride in crystalline form.

N-ethyl-3-piperidyl-phenylcyclohexylacetate and its hydrochloride andother salts differ from the above compounds by reduction of one of therings of the diphenyl acetic acid moiety to a cyclohexyl ring. Suchreduction Was carried out in glacial acetic acid with platinum oxide togive phenylcyclohexylacetic acid. The acid was treated with thionylchloride to obtain the chloride of the acid which was then reacted withpyridine and N-ethyl-3- piperidinol. The resulting compound wasneutralized, extracted with ether and dried. After removing the ether,vacuum distillation gave the desired base. The hydrochloride of theabove base was formed by dissolving the base in ether and addingethereal hydrochloric acid. The methobromide of the above base wasformed by dissolvingthe above base in ethyl alcohol and addingmethylbromide which is allowed to stand until the reaction is completed.The mixture was then concentrated and the volatiles were removed.

N ethyl 3 piperidyl benzilate hydrochloride differs from the precedingcompounds by the addition of a hydroxy group to the diphenylacetic acidmoiety. N- ethyl-3-chloro-piperidine, benzilic acid and isopropanol wererefluxed together, filtered and concentrated in vacuo. The concentratewas dissolved acidified and the unreacted acid was removed with ether.After neutralizing the aqueous layer of the mixture, the product wasextracted with ether and the solution was dried. The ether was removedand the free base was obtained by vacuum distillation. The hydrochloridewas made by treating the free base with ethereal hydrochloric acid.

N-ethyl-3-piperidyl-9-fluorene carboxylate was formed by refluxing9-fluorene carboxylic acid chloride and N- ethyl-3-hydroxy piperidine inpyridine. A large excess of water was added to the refluxed mixture andthe desired product was extracted from the mixture with ether. Themixture was distilled and the distillate was treated with anhydrousether and hydrochloric acid. The precipitate was crystallized fromacetone.

N-ethyl-3-piperidyl-9-xanthene carboxylate was made by refluxingxanthene-9-carboxylic acid and N-ethyl-3- chloro-piperidine inisopropanol. The residue was dissolved in hydrochloric acid and wasextracted with ether.

The acid layer is made alkaline and again extracted with ether and etherthen removed. The residue was heated, dissolved and acidified to form aprecipitate. After removal of solvent, the precipitate was crystallizedfrom isopropanol.

As used in the present application, the word ester includes both theesters in the free state and esters combined with, or with various addedacids to form salts.

The following examples for illustrative purposes only, show how both thesubstituted acetic esters of N-ethyl- 3-piperidinol and the salts andsubstituents thereof may be prepared.

A. Preparation of N-ethyl-S-piperidyl diphenylacetate, and its relatedcompounds To obtain the free base, 34 g. (0.256 mole) of N-ethyl-3-piperidinol and 20 g. (0.22 mole) of diphenylacetyl chloride weremixed in 80 cc. of isopropanol and the solution was refluxed for twohours. The isopropanol was evaporated in vacuo at 30 mm. pressure, theresidue was dissolved in 150 cc. of water and the aqueous solution wasextracted several times with ether. The aqueous solution was thenneutralized with potassium carbonate and extracted with ether. Theethereal solution was dried over anhydrous potassium carbonate and theether removed by distillation. The product was then distilled at itsboiling point l80181 C. at 0.13 mm. of mercury whereby 14 g. of a clearyellow, viscous liquid was obtained. The nitrogen content for C H NO wascalculated as 4.33% and the nitrogen content found was 4.21%. Thestructural formula for the free base is:

Q II I 0- o S Q N A mixture of 4.5 g. (0.02 mole) of diphenylacetylchloride and 2.6 g. (0.02 mole) of N-ethyl-3-piperidinol were dissolvedin 50 cc. of acetone and refluxed for three hours. The precipitate wasfiltered out and washed. The precipitate was then dissolved in isopropylalcohol and recrystallized, a single recrystallization yielding N-ethyl-3-piperidyl-diphenylacetate hydrochloride melting at 173174 C. Theyield was 4.2 g. (60% of theoretical). The salt is water soluble andether insoluble and in water and in alcohol.

has a high melting point. The structural formula for the above salt is:

The chlorine content for C21H2 ClNO (01' C21H25NO21HC1) i r 3 S 2 /N IC2H5 C s The calculated iodine content of C H NIO is 27.3% and thecontent found was 27.7%. The calculated nitrogen content of the abovecompound is 3.04% and the content found was 2.98%.

B. Preparation of N-methyl-3-piperidyl-diphenylacetate hydrochloride,and its related compounds 3-hydroxy pyridine was catalytically reduced(by the method of Chen-Heng Kao disclosed in Volume 44 of ChemicalAbstracts, page 3993) to 3-hydroxy-piperidine with a boiling point of67-69 C. at 2 mm. of mercury pressure. 9.0 g. (0.09 mole) of3-hydroxy-piperidine were mixed with 13.1 g. (0.25 mole) of 88% formicacid and 8.9 g. (0.11 mole) of 37% formaldehyde solution and the mixturewas refluxed for twenty-four hours. After addition of 5 ml. ofconcentrated hydrochloric acid, the mixture was distilled at 30 mm.mercury pressure to remove all volatiles. The residue was dissolved in20 ml. water and the solution was saturated with potassium hydroxide.The solution was then extracted with ether and the ether was removed bydistillation. N-methyl-3- hydroxy-piperidine was obtained bydistillation and had a boiling point of 81 C. at 15 mm. of mercury. Theyield was 7.0 g. (67% of theoretical). The N content for C H NO wascalculated as 11.92% and a content of 11.75% was found.

To obtain N-methyl-3-piperidyl-diphenylacetaite, 4.5 g. ofN-methyl-3-l1ydroxy-piperidine (0.039 mole) was mixed with 4.0 g. ofdiphenyl-acctylchloride (0.039 mole) and 50 cc. of dry pyridine whichwas used as a solvent and was therefore in large molar excess. Themixture was refluxed for four hours and 200 ml. of water containing 30g. of sodium bicarbonate was added. The solution was extracted withether and dried with potassium carbonate. The ether was removed bydistillation and the desired product was obtained by distilling at 0.06mm. of mercury. The boiling point of the product was 163" C. and 3.0 g.of N-methy1-3-piperidyl-diphenylacetate was obtained. The free base is:

The free base was dissolved in ether and ethereal hydrochloric acidsolution was added to obtain 2.7 g. of the crystalline hydrochloride.The product was recrystallized from hot acetone and had a melting pointof 193 194 C. For C H ClNO a Cl content of 10.29% and an N content of4.06 were calculated. A Cl content of 10.31% and an N content of 4.13%were found. The structural formula is:

O .HCl

From the above examples it will be apparent that various other oniumcompounds can be prepared, such compounds being of the character inwhich the electronic relations provide one or more so-called loneelectronic pairs which give a central atom a valence greater than itsnormal value. Hence, the type compound can be expressed by thestructural formula:

where R and R are lower alkyl radicals and X is an inorganic radicalsuch as a halogen, sulfate or other similar radical.

In the abovecompounds, however, it is preferred that R be an ethyl andthat R be a lower alkyl radical, for the uses to which the presentcompounds are to be put.

C. Preparation of N-ethyl-S-piperidyl-phenylcyclohexylacetate, and itsrelated compounds Diphenylacetic acid was reduced (by the method ofSmith and Alderman, volume 67 J.A.C.S. page 272) in glacial acetic acidwith platinum oxide to obtain phenylcyclohexylacetic acid which wastreated with thionyl chloride to obtain phenylcyclohexylacetyl chloride,boiling point of 133-134 C. at 4 mm. mercury pressure. A mixture of 41.2g. (0.175 mole) of the above acid chloride, 200 ml. anhydrous pyridine(as a solvent having no quantitative relation to the reactants) and 22.6g. (0.175 mole) of N-ethyl-3-piperidinol was refluxed for six hours. Thereaction product was neutralized by addition of 1 liter of 5% of sodiumbicarbonate solution. The oily layer was extracted with ether and theextract dried with potassium carbonate. The ether was distilled olf andthe residue was distilled at 0.55 mm. of mercury. The product boiled at172-174 C. and a yield of 45.3 g. (78.9% of theoretical) ofN-ethyl-3-piperidyl-phenylcyclohexyl-acetate was obtained. Thestructural formula for the free base is:

O H 0 S C luHu N jzHfi 10.0 g. of the above intermediate was dissolvedin anhydrous ether and treated with an ethereal solution of hydrochloricacid. The oily yellow product was treated with acetone to obtain a whitecrystalline precipitate melting at 208215 C. The product wasrecrystallized from isopropyl alcohol and had a melting point of 214-216 C. A yield of 10.2 g. was obtained which is 93% of theoretical.Based on the formula C H ClNO, the content of Cl was calculated to be9.72% and the con- 6 tent of N was calculated to be 3.82%. The CIcontent of 9.50% and N content of 3.55% were found. The structuralformula of N-ethyl-3-piperidylphenylcyclohexylacetate hydrochloride is:

O H II I 0-0-0 8 (Hit N (52155 .HCl.

The methobromide derivative of the above base was obtained by dissolving15.3 g. (0.046 mole) of the above intermediate in cc. of cold ethylalcohol to which 15.2 g. (0.16 mole) of methyl bromide was added. Themixture was placed in a closed citrate bottle and allowed to stand forone hundred forty-four hours at room temperature. The mixture was thenconcentrated at 30 mm. of mercury pressure and a yellow oily product wasobtained. All of the volatiles were removed from the product in a vacuumdesiccator at 2 mm. of mercury. A white powder was obtained which ishygroscopic and the melting point thereof, which was determined in asealed tube, was found to be 126-127 C. A yield of 14.3 g. (73% oftheoretical) was obtained. For the formula C H BrNO Br content of 18.83%and N content of 3.31% were calculated. Br content of 18.49% and Ncontent of 3.27% were found. The structural formula forN-ethyl-3-piperidyl-phenylcyclohexylacetate methobromide is: l

D. Preparation of N-ethyl-3-piperidyl benzilate, and its relatedcompound N-ethyl-3-chloropiperidine was prepared according to the methodof Fuson and Zirkle described in volume 70, J.A.C.S., page 2760. 12.0 g.(0.081 mole) of N-ethyl-3- chloropiperidine was mixed with 18.6 g.(0.081 mole) of benzilic acid and 80 cc. of anhydrous isopropyl alcoholas a solvent. The mixture was refluxed for seventy-two hours. Thesolution was then filtered and concentrated at 30 mm. of mercury. Theconcentrate was dissolved in water, acidified with hydrochloric acid andextracted with ether to remove the unreacted benzilic acid.

The aqueous layer was neutralized with sodium bicarbonate and theproduct was extracted with ether. The etheral solution of the productwas dried with potassium carbonate, the ether was removed bydistillation and the residue was distilled at 0.12-0.18 mm. of mercury,the boiling point being 194-198" C. A yield of 16.5 g. 60% oftheoretical) of N-ethyl-B-piperidyl-benzilate was obtained. Thestructural formula is:

6.4 g. of the above free base was dissolved in acetone and etherealhydrochloric acid added. 6.2 g. of white crystals were obtained, thecrystals having a melting point of 186-187 C. The yield was 86% oftheoretical. For the formula C H ClNO a chlorine content of 9.45%

was calculated and the content found was 9.29%. A nitrogen content of3.72% was calculated and the nitrogen content found was 3.62%. Thestructural formula for N-ethyl-3-piperidyl-benzilate hydrochlorideformula is:

It will be apparent from the various examples given above that otherpiperidyl esters may be made with different acid moieties.

E. Preparation of N-ethyl-3-piperidyl-9- uorenecarboxylate A mixture of14.0 g. (0.064 mole) of 9-fluorenecarboxylic acid chloride and 9.0 g.(0.074 mole) of N-ethyl-3-hydroxy piperidine was dissolved in 60 cc.pyridine and was refluxed for one hour. The product was cooled and mixedwith 400 cc. of water. The oily yellow precipitate was extracted withether and the extract was dried over potassium carbonate. The extractwas distilled at 0.3 mm. of mercury at 205-215" C. to obtain 2.0 g. ofdistillate.

The distillate was dissolved in anhydrous ether and acidified withethereal hydrochloric acid. A gummy precipitate formed from which theether was decanted. The precipitate was crystallized from acetone toyield 0.1 g. of the desired product (0.4% of theoretical), melting at226227 C. For the formula C H C1NO a Cl content of 9.94% was calculatedand Cl content of 9.97% was found. The structural formula of the abovebase is:

F. Preparation of N-ethyl-3-piperidyl-9-xanthene carboxylate A mixtureof 11.0 g. (0.049 mole) of xanthene-9- carboxylic acid and 7.2 g. (0.049mole) of N-ethyl-3- chloropiperidine was dissolved in 50 cc. of dryisopropyl alcohol and refluxed for seventy-two hours. The mixture wasthen concentrated at 30 mm. pressure.

The residue was partially dissolved in dilute aqueous hydrochloric acidand extracted twice with ether. The aqueous layer was made alkaline withsodium hydroxide solution and extracted with ether. The extract wasdried over potassium carbonate and the ether was removed bydistillation. The residue was first heated over a bath water under avacuum of 2 mm. mercury to remove low boiling point materials and wasthen dissolved in anhydrous ether and acidified with etherealhydrochloric acid. A gummy precipitate formed from which the ether wasdecanted. The precipitate was crystallized in hot isopropyl alcohol toyield 4.1 g. (22% of theoretical) of the desired product. The producthad a melting point of 226227 C. For the formula C H ClNO a Cl content9.51% was calculated and Cl content of 9.34% found. An N content 3.75%was calculated and N content 3.74% found. The structural formula of theabove free base is:

@Oig/ G. Preparation of N-ethyl-3-piperidyl phenylcyclopentylacetate andhydrochloride thereof 0 oon o O 2 1 .1101

To 114 g. (0.88 mole) of N-ethyl-3-hydroxypiperidine in 500 cc. ofanhydrous benzene was added 196.6 g. (0.88 mole) ofphenylcyclopentylacetyl chloride in 500 cc. of benzene in the presenceof 107 g. (1.06 moles) of triethylamine. The reaction mixture wasstirred at 65-75 C. for 4 hours and the triethylamine hydrochlorideremoved by filtration. The filtrate was distilled and the basic estercollected at 154-17-8 C. (0.04 mm), yield 220 g. (79% The hydrochloridesalt was formed in acetone by the addition of ethereal hydrochloricacid. The crude salt was recrystallized repeatedly from acetone, M.P.181- 183 C.

Analysis.-Calcd. for C H ClNO 01, 10.10; N, 3.98. Found: Cl, 10.13; N,4.12.

It has been found that the present compositions are nontoxic andalleviate or stop smooth muscle spasm regardless of its origin, and thatthe compounds are free from the undesirable reactions producing pupildilation, dryness of mouth and other undesirable side effects.

It is well known that the anti-spasmodic activity of compounds such asthe salts disclosed herein, is due to the ester portion of the moleculeand not to the acid used to form the salts. Hence, it will be understoodthat various salts other than those herein disclosed, may be readilymade. Such other additional salts include particularly the hydrobromide,maleate, succinate, tartrate, benzoate and phosphate, and are readilyprepared from the free base and the corresponding acid in solvents suchas acetone, benzene, ether type compounds, ethanol, isopropanol, andother alcohols.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

. N-lower alkyl-3-piperidyl-phenyl-cyclohexyl acetate. 2.N-ethyl-3-piperidyl-phenyl-cyclohexyl acetate.

3. N-lower alkyl-3-piperidyl-9-fiuorene carboxylate.

4. N-ethyl-3-piperidyl-9-fiuorene carboxylate.

g. N-lower alkyl-3-piperidyl-9-xanthene carboxylate. 7

. N-ethyl-3-piperidyl-9-xanthene carboxylate.

. N-lower acewherein R is lower alkyl, R is a member of the group 9consisting of phenyl, cyclopentyl, cyclohexyl and Z-thienyl, R is amember of the group consisting of cyclopentyl, cyclohexyl, Z-thienyl andgroups in which represents a member of the group consisting of fluorenyland xanthenyl, and nontoxic pharmaceutically acceptable acid additionsalts and nontoxic pharmaceutically acceptable lower alkyl halidequaternary ammonium salts thereof.

References Cited in the file of this patent UNITED STATES PATENTS2,265,184 Miescher et a1. Dec. 9, 1941 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 2,995,560 August 8, 1961 John H.Biel It is hereby certified that error appears in the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 6, line 55, for "etheral" read ethereal lines 64 to 68, theformula should appear as shown below instead of as in the patent:

Signed and sealed this 2nd day of January 1962.

(SEAL) Attest:

DAVID L, LADD ERNEST w, SWIDER Attesting Officer Commissioner of Hatents

9. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA